Drug addiction is marked by a conditioned physiological response and intense craving when abusers encounter stimuli associated with the drug's rewarding effects. Memory of these drug-paired cues is highly resistant to extinction and is a major contributor to relapse. Understanding on a molecular and cellular level how these factors promote relapse, despite negative consequences, has become a major focus of addiction research. Recently, we have reported the surprising finding that both histone modifications and direct covalent modification of DNA underiy normal memory formation, as well as the maintenance of lasting memories. The goal of the current project is to study the epigenetic basis of cocaine addiction, with a specific emphasis on understanding the epigenetic mechanisms active during drug-associated memory formation and relapse to drug seeking. During the course of this project, I will investigate the hypothesis that epigenetic modifications are important for the formation, retrieval and reconsolidation of cocaine-associated memories. This will be achieved by studying the specific enzymes responsible for catalyzing histone modifications and cytosine methylation through gene expression analysis, the use of transgenic mice and intra-GNS infusions of drugs that inhibit or augment these enzymes. In addition, I will investigate the specific genes that are methylated, as well as the associated chromatin modifications using a variety of techniques, including methylation microarray, bisulfite sequencing and chromatin immunoprecipitation (ChIP). By understanding the role of the epigenome in the establishment and maintenance of drug addiction, novel sites of therapeutic intervention may be discovered.